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Canadian Journal of Cardiology

Can We Eliminate Low-Density Lipoprotein Cholesterol-Related Cardiovascular Events Through More Aggressive Primary Prevention Therapy?

Published:March 01, 2018DOI:https://doi.org/10.1016/j.cjca.2018.02.027

      Abstract

      Intravascular levels of low-density lipoprotein cholesterol (LDL-C) at approximately ≤ 0.6 mmol/L are likely to minimize, and perhaps eliminate, LDL-C-related vascular toxicity while having no effect on essential, intracellular cholesterol homeostatic pathways, according to accumulated knowledge from basic science. Randomized clinical trials, observational reports, and Mendelian randomization trials are also forcing a reconsideration of what “normal” LDL-C means. Recent trials of secondary prevention have substantiated that such levels are safe and associated with a decreased risk of cardiovascular events (CVEs) compared with patients with higher levels of LDL-C. Similarly, treatment to this low range is associated with regression and stabilization of established atherosclerosis. Primary prevention trials also show that low levels of LDL-C are safe and associated with decreased risk of CVEs through cholesterol-lowering in adults with LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with other cardiovascular risks. Although there are no randomized clinical outcome trials of familial hypercholesterolemia patients, such patients have very high, lifetime risk of CVE, and registry studies show that LDL-C reduction has nearly normalized their CVE rates. The possibility of familial hypercholesterolemia should be considered if LDL-C is > 4.5 and > 4.0 mmol/L at ages 18-39 years and younger than 18 years, respectively. On the basis of these convergent and internally consistent lines of evidence, in this article we speculate on a translational paradigm aimed at eliminating LDL-C-related CVEs through aggressive primary prevention strategies that are already proven and well accepted in principle.

      Résumé

      D’après les connaissances acquises dans le domaine des sciences fondamentales, les concentrations intravasculaires de cholestérol à lipoprotéines de faible densité (C-LDL) égales ou inférieures à environ 0,6 mmol/l sont de nature à réduire au minimum, voire à éliminer la toxicité vasculaire liée au C-LDL tout en étant sans effet sur les voies homéostatiques essentielles du cholestérol intracellulaire. Les essais cliniques à répartition aléatoire, les rapports de cas clinique et les essais à randomisation mendélienne amènent également à reconsidérer ce que signifie une concentration de C-LDL « normale ». Les essais cliniques sur la prévention secondaire réalisés récemment sont venus confirmer que de telles concentrations sont sans danger et sont associées à une diminution du risque d'événement cardiovasculaire comparativement aux patients présentant une concentration de C-LDL plus élevée. De même, le traitement visant l'atteinte de cette plage de valeurs faibles est associé à la régression et à la stabilisation de l'athérosclérose installée. Les essais cliniques sur la prévention primaire montrent également que les faibles concentrations de C-LDL sont sans danger et associées à une réduction du risque d'événements cardiovasculaires par l'intermédiaire de l'abaissement du taux de cholestérol chez les adultes présentant un taux de C-LDL ≥ 3,5 mmol/l, ou quand les valeurs sont < 3,5 mmol/l en association avec d'autres risques cardiovasculaires. Aucun essai clinique à répartition aléatoire n’a été mené sur les effets chez les patients atteints d'hypercholestérolémie familiale, mais on sait que ces individus présentent un risque très élevé d'événements cardiovasculaires durant leur vie, et les études fondées sur des registres montrent que la réduction du taux de C-LDL permet pratiquement de normaliser la fréquence des événements cardiovasculaires dans cette population. La possibilité d'une hypercholestérolémie familiale devrait être envisagée si le taux de C-LDL est > 4,5 et > 4,0 mmol/l chez des patients âgés de 18 à 39 ans et de moins de 18 ans, respectivement. Dans le présent article, nous nous appuyons sur ces sources de données probantes convergentes et intrinsèquement cohérentes pour réfléchir à un paradigme translationnel visant à éliminer les événements cardiovasculaires liés au C-LDL par des stratégies de prévention primaire énergiques qui ont déjà fait leurs preuves et dont le principe est bien accepté.
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